Synthesis and characterization of fluorescent ligands for the norepinephrine transporter: Potential neuroblastoma imaging agents

Radiolabeled m-iodobenzylguanidine (MIBG) is a tumor-seeking radioactive dr ug used in the diagnosis and treatment of pheochromocytomas and neuroblasto mas. It is transported into the tumor cells by the neuronal norepinephrine (NE) transporter (NET) which is expressed in almost all neuroblastoma cells . Here, we describe the synthesis and some pharmacological properties of a series of fluorescent compounds structurally related to the NET substrate, MIBG, or to the NET inhibitors, (-)-(2R,3S)-cocaine and nisoxetine. Three o f 10 synthesized fluorescent compounds, 1-(1-naphthylmethyl)guanidinium sul fate (1), 1-[2-(dibenz[b,f]azepin-5-yl)ethyl]guanidinium sulfate (2), and ( 2R,3S)-2 beta-ethoxycarbonyl-3 beta-tropanyl 5-(dimethylamino)naphthalene-1 -sulfonate (6), exhibited high affinity (IC50 about 50 nM) for the NET. The nisoxetine derivatives 8 (rac-N-[(3-methylamino-1-phenyl)propyl]-5-(dimeth ylamino)-1-naphthalene-sulfonamide) and 9 (rac-4-[(3-methylamino-1-phenyl)p ropyl]amino-7-nitro-2,1,3-benzoxadiazole) and especially the guanidine deri vative 4 (1-[4-(4-phenyl-1,3-butadienyl)benzyl]guanidinium sulfate) which a re characterized by intermediate affinity for the NET (IC50 370-850 nM) cau sed significant and nisoxetine-sensitive cell fluorescence. At least the gu anidine derivative 4 might represent a potentially useful agent for imaging of neuroblastoma cells.